Endoprosthesis coating

ABSTRACT

An endoprosthesis, such as a stent, includes a chemical tie layer formed of polymer that enhance adherence of a coating, e.g. a drug eluting polymer coating, to a stent surface, e.g. made of ceramic.

TECHNICAL FIELD

The invention relates to endoprosthesis coating.

BACKGROUND

The body includes various passageways including blood vessels such asarteries, and other body lumens. These passageways sometimes becomeoccluded or weakened. For example, they can be occluded by a tumor,restricted by plaque, or weakened by an aneurysm. When this occurs, thepassageway can be reopened or reinforced, or even replaced, with amedical endoprosthesis. An endoprosthesis is an artificial implant thatis typically placed in a passageway or lumen in the body. Manyendoprostheses are tubular members, examples of which include stents,stent-grafts, and covered stents.

Many endoprostheses can be delivered inside the body by a catheter.Typically the catheter supports a reduced-size or compacted form of theendoprosthesis as it is transported to a desired site in the body, forexample the site of weakening or occlusion in a body lumen. Uponreaching the desired site the endoprosthesis is installed so that it cancontact the walls of the lumen.

One method of installation involves expanding the endoprosthesis. Theexpansion mechanism used to install the endoprosthesis may includeforcing it to expand radially. For example, the expansion can beachieved with a catheter that carries a balloon in conjunction with aballoon-expandable endoprosthesis reduced in size relative to its finalform in the body. The balloon is inflated to deform and/or expand theendoprosthesis in order to fix it at a predetermined position in contactwith the lumen wall. The balloon can then be deflated, and the catheterwithdrawn. Stent delivery is further discussed in Heath, U.S. Pat. No.6,290,721.

It is sometimes desirable for an endoprosthesis to contain a therapeuticagent, or drug which can elute into the body in a predetermined manneronce the endoprosthesis is implanted.

SUMMARY

In an aspect, the invention features an endoprosthesis with a bodyincluding a ceramic on a surface thereof, a tie layer adhered to theceramic, and a polymeric coating adhered to the tie layer.

In another aspect, the invention features a method of forming anendoprosthesis. The method includes forming a ceramic and a non-ceramic,non-metal overlayer on the ceramic such that, the ceramic has an Sdr ofabout 10 or less, and the layer is covalently bonded to the ceramic, orthe ceramic has an Sdr of about 100 or greater, and the layer isnon-covalently adhered to the ceramic, or the ceramic has an Sdr betweenabout 10 and 100 and the layer is non-covalently adhered or covalentlybonded to the ceramic.

Embodiments may include one or more of the following features. Theceramic has an Sdr of about 10 or less and an Sq of about 10 or less andthe tie layer is covalently bonded to the ceramic. The ceramic has aglobular morphology. The ceramic has surface oxygen content of about 80%or more and the tie layer is covalently bonded to the ceramic. Theceramic has an Sdr of about 120 to 200 and an Sq of about 20 or more andthe tie layer is non-covalently adhered to the ceramic. The ceramic hasa defined grain morphology. The ceramic has a surface oxygen content ofabout 80% or less and the tie layer is non-covalently adhered to theceramic. The ceramic is an oxide. The ceramic is IROX. The tie layer iscovalently bonded to the ceramic. The tie layer is non-covalentlyadhered to the ceramic. The tie layer is selected from silanes,phosphonates, and titanates. The polymeric coating includes a drug. Thepolymeric coating is adhered to the tie layer by covalent bonding. Thepolymeric coating is adhered to the tie layer by non-covalent adherence.The polymeric coating and the ceramic has an adhesion increased about10% or greater by the tie layer. The polymeric coating and the ceramichas an adhesion increased about 50% or greater by the tie layer.

Embodiments may also include one or more of the following features. Themethod further includes forming a polymer layer on the overlayer. Theceramic having the Sdr of about 10 or less has a globular morphology.The ceramic having the Sdr of about 100 or greater has a defined grainmorphology. The ceramic is an oxide. The ceramic is IROX. The covalentbond is formed through oxygen moieties of the ceramic. The overlayer isa silane, phosphate or titanate. The polymer layer includes a drug. Thepolymer layer and the ceramic has an adhesion increased about 10% orgreater by the overlayer. The polymer layer and the ceramic has anadhesion increased about 50% or greater by the overlayer through thecovalent bond.

Aspects and/or embodiments may include one or more of the followingadvantages. An endoprosthesis, such as a stent, can be provided with apolymer coating, such as a drug eluting coating, that is stronglyadhered to the stent to reduce flaking or delamination. The stent caninclude a ceramic material, and the polymer coating can be a materialthat has desirable drug release characteristics but non-optimal adhesioncharacteristics to the ceramic material. The adhesion can be enhancedwithout modifying drug delivery or biocompatibility characteristics. Thestent can include a chemical tie layer directly on a ceramic surface,e.g. IROX, that has good adhesive characteristics to the ceramic. Thetie layer also has good adhesive characteristics to a polymer. The tielayer can be selected in coordination with the morphology andcomposition of the ceramic. For example, for a relatively smoothmorphology, the adhesive characteristics of the tie layer to the ceramicare selected to be increased, e.g. by covalent bonding. The adhesionstrength, e.g. amount of covalent bonding or the degree ofhydrophilicity can be increased, e.g., by increasing the concentrationof bonding moieties at the surface, by e.g. increasing the oxygencontent at the surface.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1C are longitudinal cross-sectional views illustrating deliveryof a stent in a collapsed state, expansion of the stent, and deploymentof the stent.

FIG. 2A is a perspective view of a stent.

FIG. 2B is a schematic cross-sectional view of a portion of a stent.

FIG. 3 is a schematic cross-sectional view of a portion of a stent.

FIGS. 4A and 4B are micrographs of IROX morphologies.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Referring to FIGS. 1A-1C, a stent 20 is placed over a balloon 12 carriednear a distal end of a catheter 14, and is directed through the lumen 16(FIG. 1A) until the portion carry the balloon and stent reaches theregion of an occlusion 18. The stent 20 is then radially expanded byinflating the balloon 12 and compressed against the vessel wall with theresult that occlusion 18 is compressed, and the vessel wall surroundingit undergoes a radial expansion (FIG. 1B). The pressure is then releasedfrom the balloon and the catheter is withdrawn from the vessel (FIG.1C).

Referring to FIG. 2A, the stent 20 includes a plurality of fenestrations22 defined in a wall 23. Stent 22 includes several surface regions,including an outer, or abluminal, surface 24, an inner, or adluminal,surface 26, and a plurality of cut-face surfaces 28. The stent can beballoon expandable, as illustrated above, or self-expanding stent. Inembodiments, the stent includes a body made of e.g. a metal such asstainless steel, chrome, nickel, cobalt, tantalum, superelastic alloyssuch as nitinol, cobalt chromium, MP35N, and other metals. Suitablestent materials and stent designs are described in Heath '721, supra.

Referring to FIG. 2B, the stent 20 includes a body 21. On the abluminaland adluminal surfaces 24, 26 the stent includes a layer 23 of amaterial effective to enhance stent function, such as a ceramic, e.g.iridium oxide (IROX), that enhances stent endothelialization. Theabluminal surface 24 further includes a coating 25 of a polymer thatenhances function by, e.g. eluting a drug. The adherence of the coating25 to the stent is enhanced by a chemical tie layer 27 which is boundtightly to the ceramic layer 23. The tie layer 27 includes a compound,e.g., a polymer, with good adhesion properties to both the ceramic andthe polymer in the coating 25. For example, in embodiments, the tielayer 27 includes compounds such as silanes which can form Si—O bondswith a ceramic surface or have non-covalently adhesive interactions withthe surface. The silanes can be modified or derivatized forcompatibility with the drug eluting polymer (“DEP”) coating 25. Forexample, the silanes can be modified with moieties that adjusthydrophobicity/hydrophilicity for compatibility with the polymer coating25 or moieties that cross-link with the polymer coating 25. A suitabledrug eluting polymer is SIBS. Other suitable materials for layers 23,25, and 27 are discussed below.

Referring to FIG. 3, an expanded schematic view of a region of a stent,the stent body 21 includes at least one surface upon which a ceramic 23lies. The surface of the ceramic includes oxygen moieties such as —OHand —O⁻. The hydrophilicity of the surface can be selected bycontrolling the surface concentration of oxygen moieties. A tie layer 27formed of compounds 300 adheres to the ceramic through interactions orlinks 30 and a polymeric coating 25 formed of polymers 320 adheres tothe tie layer through interactions or links 32. Links 30 and 32 caneither be covalent bonding or a non-covalent adhesive interactions, suchas electrostatic interactions, van de Waals forces or hydrogen bonds.

In embodiments, compound 300 is selected from a non-metal, non-ceramicmaterial such as silanes, phosphonates, bisphosphonates, titanates, ormixtures or derivatives thereof. The compound 300 can adhere to theceramic surface through one or more covalent bonds, such as Si—O, P—O orTi—O bonds. In particular embodiments, di or tripodal linkages enhancethe efficiency of the tie layer adhesion and thus the adhesion of thepolymer coating to the ceramic.

In embodiments, compound 300 is derivatized to be compatible withhydrophilicity/hydrophobicity of the ceramic surface. For example, ifthe ceramic surface is hydrophilic, compound 300, can include somehydrophilic functional groups such as amine, hydroxyl, or carboxylicgroups. In embodiments, lactic acid groups are used to enhancenon-covalent adhesion to a hydrophilic surface. If the ceramic surfaceis hydrophobic, the compound 300 can include some hydrophobic functionalgroups such as alkyl, alkenyl, alkynyl, or aromatic groups. In someembodiments, compound 300 is a polymer precursor and may be polymerizedto form a polymeric tie layer by, e.g., using plasma techniques such asplasma enhanced chemical vapor deposition (“PECVD”). In otherembodiments, compound 300 is a polymer before it is applied to theceramic surface. Suitable polymers or polymer precursors includepolysilanes such as poly(phenylmethylsilane) and alkoxysilanes such asaminopropyltriethoxysilane and phenethyltrimethoxysilane. Compounds 300may be applied to the ceramic surface by, e.g., rolling, dipping,spraying, or vapor deposition.

In embodiments, the tie layer is selected in coordination with themorphology and/or chemical compositions of the ceramic layer. Referringto FIGS. 4A and 4B, micrographs of IROX coatings of different morphologyare illustrated. Referring particularly to FIG. 4A, a relatively lowroughness, smoother globular surface morphology that can enhanceendothelialization is illustrated. Referring particularly to FIG. 4B, adefined grain, high roughness morphology is illustrated. The definedgrain morphology provides increased surface area, and deep featureswhich can enhance coating adhesion, whereas the globular morphologyprovides smaller surface area, which generally reduces adhesion. Inembodiments, the tie layer is selected for stronger adhesion by, such ascovalent bonding on smooth surfaces. To enhance covalent bonding, thesurface compositions of the ceramic are formulated to such that theyhave increased bonding moieties in terms of oxygen content at thesurface. Smoother globular surface morphology provides a surface whichis tuned to facilitate endothelial growth by selection of its chemicalcomposition and/or morphological features. Certain ceramics, e.g.oxides, can reduce restenosis through the catalytic reduction ofhydrogen peroxide and other precursors to smooth muscle cellproliferation. The oxides can also encourage endothelial cell growth toenhance endothelialization of the stent. As discussed above, when astent, is introduced into a biological environment (e.g., in vivo), oneof the initial responses of the human body to the implantation of astent, particularly into the blood vessels, is the activation of whiteblood cells. This activation causes a release of hydrogen peroxide,H₂O₂. The presence of H₂O₂ may increase proliferation of smooth musclecells and compromise endothelial cell function, stimulating theexpression of surface binding proteins which enhance the attachment ofmore inflammatory cells. A ceramic, such as IROX can catalyticallyreduce H₂O₂. The smoother globular surface morphology of the ceramic canenhance the catalytic effect and enhance growth of endothelial cells.Defined grain morphologies also allow for greater freedom of motion andare less likely to fracture as the stent is flexed in use and thus thematrix coating resists delamination of the ceramic from an underlyingsurface and reduces delamination of a possible overlaying coating. Thestresses caused by flexure of the stent, during expansion or contractionof the stent or as the stent is delivered through a tortuously curvedbody lumen increase as a function of the distance from the stent axis.As a result, in embodiments, a morphology with defined grains isparticularly desirable on abluminal regions of the stent or at otherhigh stress points, such as the regions adjacent fenestrations whichundergo greater flexure during expansion or contraction.

The morphology of the surface of the ceramic is characterized by itsvisual appearance, its roughness, and/or the size and arrangement ofparticular morphological features such as local maxima. Referringparticularly to FIG. 4A, in embodiments, the surface is characterized bya more continuous surface having a series of shallow globular features.The globular features are closely adjacent with a narrow minima betweenfeatures. In embodiments, the surface resembles an orange peel. Thediameter of the globular features is about 100 nm or less, and the depthof the minima, or the height of the maxima of the globular function ise.g. about 50 nm or less, e.g. about 20 nm or less.

Referring particularly to FIG. 4B, in embodiments, the surface ischaracterized by definable sub-micron sized grains. The grains have alength, L, of the of about 50 to 500 nm, e.g. about 100-300 nm, and awidth, W, of about 5 nm to 50 nm, e.g. about 10-15 nm. The grains havean aspect ratio (length to width) of about 5:1 or more, e.g. 10:1 to20:1. The grains overlap in one or more layers. The separation betweengrains can be about 1-50 nm. In particular embodiments, the grainsresemble rice grains. In other embodiments, the surface hascharacteristics between high aspect ratio definable grains and the morecontinuous globular surface and/or has a combination of thesecharacteristics. For example, the morphology can include a substantiallyglobular base layer and a relatively low density of defined grains. Inother embodiments, the surface can include low aspect ratio, thin planarflakes. The morphology type is visible in FESEM images at 50 KX.

The roughness of the surface can also be characterized by the averageroughness, Sa, the root mean square roughness, Sq, and/or the developedinterfacial area ratio, Sdr. The Sa and Sq parameters represent anoverall measure of the texture of the surface. Sa and Sq are relativelyinsensitive in differentiating peaks, valleys and the spacing of thevarious texture features. Surfaces with different visual morphologiescan have similar Sa and Sq values, indicating the insensitivity of theSa and Sq parameters. For a surface type, the Sa and Sq parametersindicate significant deviations in the texture characteristics. Sdr isexpressed as the percentage of additional surface area contributed bythe texture as compared to an ideal plane the size of the measurementregion. Sdr further differentiates surfaces of similar amplitudes andaverage roughness. Typically Sdr will increase with the spatialintricacy of the texture whether or not Sa changes.

In embodiments, the ceramic has a defined grain morphology. The Sdr isabout 100 or more, e.g. about 120 to 200. In addition or in thealternative, the morphology has an Sq of about 20 or more, e.g. about 20to 30. In other embodiments, the ceramic has a globular surfacemorphology. The Sdr is about 10 or less, e.g. about 1 to 8. The Sq isabout 10 or less, e.g. about 1 to 5. In still other embodiments, theceramic has a morphology between the defined grain and the globularsurface, with Sdr and Sq values between the ranges above, e.g. an Sdr ofabout 1 to 200 and/or an Sq of about 1 to 30. The Sa, Sq, and Sdr can becalculated from AFM data. The uniformity of the morphology can be withinabout +/−20% or less, e.g. +/−10% or less within a 1 μm×1 μm square. Ina given stent region, the uniformity is within about +/− about 10%, e.g.about 1%. For example, in embodiments, the ceramic exhibits highuniformity over the entire surface side of the stents, such as theentire abluminal or adluminal surface, or a portion of a surface side,such as the center 25% or 50% of the surface. The high uniformityprovides predictable, tuned therapeutic and mechanical performance ofthe ceramic.

In embodiments, the ceramics are also characterized by surfacecomposition, composition as a function of depth, and crystallinity. Inparticular, the amounts of oxygen or nitride in the ceramic is selectedfor a desired catalytic effect on, e.g., the reduction of H₂O₂ inbiological processes. The composition of metal oxide or nitride ceramicscan be determined as a ratio of the oxide or nitride to the base metal.In particular embodiments, the ratio is about 2 to 1 or greater, e.g.about 3 to 1 or greater, indicating high oxygen content of the surface.In other embodiments, the ratio is about 1 to 1 or less, e.g. about 1 to2 or less, indicating a relatively low oxygen composition. In particularembodiments, low oxygen content globular morphologies are formed toenhance endothelialization. In other embodiments, high oxygen contentdefined grain morphologies are formed, e.g., to enhance adhesion andcatalytic reduction. Composition can be determined by x-rayphotoelectron spectroscopy (XPS). Depth studies are conducted by XPSafter FAB sputtering. The crystalline nature of the ceramic can becharacterized by crystal shapes as viewed in FESEM images, or Millerindices as determined by x-ray diffraction. In embodiments, definedgrain morphologies have a Miller index of <101>. Globular materials haveblended amorphous and crystalline phases that vary with oxygen content.Higher oxygen content typically indicates greater crystallinity. Furtherdiscussion of ceramics and ceramic morphology and computation ofroughness parameters is in provided in U.S. patent application Ser. Nos.11/752,772 and 11/752,736 and appendices, filed May 23, 2007. Othersuitable ceramics include metal oxides and nitrides, such as of iridium,zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum andaluminum. The ceramic can be crystalline, partly crystalline oramorphous. IROX is further discussed in Alt, U.S. Pat. No. 5,980,566 andU.S. Ser. No. 10/651,562 filed Aug. 29, 2003. The ceramic layer 23 canbe, e.g. 10-50 μm in thickness.

In any of the morphologies, the tie layer can be bonded covalently oradhered non-covalently to the ceramic. In the case of globular orintermediate morphologies, the bond or adhesion strength is selected tobe enhanced. For example, if the ceramic surface is hydrophilic, the tielayer that includes hydrophilic compatible moieties is selected toenhance adhesion. In particular embodiments, the adhesion is enhanced bycovalent bonding. In embodiments, in the case of defined grainmorphologies, the tie layer can be non-covalently or covalently adhered.

The tie layer is also selected for compatibility with the polymer 320.The polymer 320 adheres to the tie layer through either covalent bondingor non-covalent interactions, such as electrostatic interactions, van deWaals forces, or hydrogen bonds, all of which are schematicallyrepresented by links 32 in FIG. 3. Similar to that discussed above, thetie layer compounds 300 can be derivatized for compatibility with theDEP. For example, if the DEP is hydrophobic, the tie layer can includehydrophobic moieties. For example, if SIBS (styrene-isobutylene-styrenecopolymer) is used, compound 300 can include phenyl groups, e.g. asphenylalkenyl silane, to enhance adherence of SIBS to the tie layer. Inparticular embodiments, for more hydrophilic polymers, the tie layer isa more hydrophilic silane, e.g. amino alkoxy silane. In particularembodiments, polymer 320 may include reactive end groups such ashydroxyl, carboxyl, halide, and amine groups which react readily withsilanes, e.g. amino alkoxy silane and as a result, the polymer iscovalently bonded to the tie layer. Examples of silanes are availablefrom Gelest, Inc. and more examples of phosphonates are disclosed by VanAlsten, Langmuir, 15, 7605-7614 (1999). PECVD of silanes is disclosed inmore detail by Long, U.S. Publication No. 2003/0170605. Formation ofsilane layer is discussed further in Duwez, Nature Nanotechnology, 1,122-125 (2006) and J. Neurophysiol 93, 1659-1670 (2005). The enhancementof polymer-ceramic adhesion due to the tie layer can be tested bystandard test methods for adhesion, e.g., Peel test, ASTM D 2197 (scrapeadhesion) or ASTM D 3359 (tape test). For example, the standard adhesiontests can tell whether a failure of an adhesive joint is cohesive oradhesive, or what fraction of material remains on a substrate, or theforce or energy required to cause the failure. More specifically, as anexample, after a standard test, the amount of polymer remaining on aceramic surface that has a tie layer can be compared to that on theceramic surface without the tie layer. In embodiments, with the chemicaltie layer, the adhesion between the polymer and the ceramic is increasedby about 10% or greater, e.g., in terms of amount of polymer remainingon the ceramic after the test. In particular embodiments, the adhesionbetween polymer and the ceramic is increased by about 50% or greater dueto the chemical tie layer. In embodiments, compatibility of twodifferent compounds or materials can be characterized by DifferentialScanning Calorimetry (DSC) miscibility test, or contact angleexperiments. In embodiments, the contact angle of the tie layer and theceramic is about 90° or less, preferably 20° or less. In embodiments,DSC analysis can examine the miscibility of two compounds by detectingchange of the glass transition peaks since incompatible mixtures willexhibit separate glass transition or melting peaks for each componentwhereas compatible mixtures will exhibit only one peak that is typicallydifferent from the individual component peaks. The drug-eluting polymeror polymer precursor can be applied to the tie layer by, e.g., rolling,dipping, spraying, or vapor deposition. In embodiments, the tie layercan be patterned to increase its surface area. Patterning is furtherdiscussed in detail in U.S. patent application Ser. No. 11/803,499 filedcontemporaneously herewith, the entire contents of which is herebyincorporated herein by reference.

Suitable drug eluting polymers may be hydrophilic or hydrophobic, andmay be selected, without limitation, from polymers including, forexample, polycarboxylic acids, cellulosic polymers, including celluloseacetate and cellulose nitrate, gelatin, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, polyanhydrides including maleicanhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinylmonomers such as EVA, polyvinyl ethers, polyvinyl aromatics such aspolystyrene and copolymers thereof with other vinyl monomers such asisobutylene, isoprene and butadiene, for example,styrene-isobutylene-styrene (SIBS), styrene-isoprene-styrene (SIS)copolymers, styrene-butadiene-styrene (SBS) copolymers, polyethyleneoxides, glycosaminoglycans, polysaccharides, polyesters includingpolyethylene terephthalate, polyacrylamides, polyethers, polyethersulfone, polycarbonate, polyalkylenes including polypropylene,polyethylene and high molecular weight polyethylene, halogeneratedpolyalkylenes including polytetrafluoroethylene, natural and syntheticrubbers including polyisoprene, polybutadiene, polyisobutylene andcopolymers thereof with other vinyl monomers such as styrene,polyurethanes, polyorthoesters, proteins, polypeptides, silicones,siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone,polyhydroxybutyrate valerate and blends and copolymers thereof as wellas other biodegradable, bioabsorbable and biostable polymers andcopolymers. Coatings from polymer dispersions such as polyurethanedispersions (BAYHDROL®, etc.) and acrylic latex dispersions are alsowithin the scope of the present invention. The polymer may be a proteinpolymer, fibrin, collage and derivatives thereof, polysaccharides suchas celluloses, starches, dextrans, alginates and derivatives of thesepolysaccharides, an extracellular matrix component, hyaluronic acid, oranother biologic agent or a suitable mixture of any of these, forexample. In one embodiment, a suitable polymer is polyacrylic acid,available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.),and described in U.S. Pat. No. 5,091,205, the disclosure of which ishereby incorporated herein by reference. U.S. Pat. No. 5,091,205describes medical devices coated with one or more polyiocyanates suchthat the devices become instantly lubricious when exposed to bodyfluids. Another polymer is a copolymer of polylactic acid andpolycaprolactone. Suitable polymers are discussed in U.S. PublicationNo. 20060038027.

The polymer is preferably capable of absorbing a substantial amount ofdrug solution. When applied as a coating on a medical device inaccordance with the present invention, the dry polymer is typically onthe order of from about 1 to about 50 microns thick. In the case of aballoon catheter, the thickness is preferably about 1 to 10 micronsthick, and more preferably about 2 to 5 microns. Very thin polymercoatings, e.g., of about 0.2-0.3 microns and much thicker coatings,e.g., more than 10 microns, are also possible. It is also within thescope of the present invention to apply multiple layers of polymercoating onto a medical device. Such multiple layers are of the same ordifferent polymer materials.

The terms “therapeutic agent”, “pharmaceutically active agent”,“pharmaceutically active material”, “pharmaceutically activeingredient”, “drug” and other related terms may be used interchangeablyherein and include, but are not limited to, small organic molecules,peptides, oligopeptides, proteins, nucleic acids, oligonucleotides,genetic therapeutic agents, non-genetic therapeutic agents, vectors fordelivery of genetic therapeutic agents, cells, and therapeutic agentsidentified as candidates for vascular treatment regimens, for example,as agents that reduce or inhibit restenosis. By small organic moleculeis meant an organic molecule having 50 or fewer carbon atoms, and fewerthan 100 non-hydrogen atoms in total.

Exemplary therapeutic agents include, e.g., anti-thrombogenic agents(e.g., heparin); anti-proliferative/anti-mitotic agents (e.g.,paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,inhibitors of smooth muscle cell proliferation (e.g., monoclonalantibodies), and thymidine kinase inhibitors); antioxidants;anti-inflammatory agents (e.g., dexamethasone, prednisolone,corticosterone); anesthetic agents (e.g., lidocaine, bupivacaine andropivacaine); anti-coagulants; antibiotics (e.g., erythromycin,triclosan, cephalosporins, and aminoglycosides); agents that stimulateendothelial cell growth and/or attachment. Therapeutic agents can benonionic, or they can be anionic and/or cationic in nature. Therapeuticagents can be used singularly, or in combination. Preferred therapeuticagents include inhibitors of restenosis (e.g., paclitaxel),anti-proliferative agents (e.g., cisplatin), and antibiotics (e.g.,erythromycin). Additional examples of therapeutic agents are describedin U.S. Published Patent Application No. 2005/0216074. Polymers for drugelution coatings are also disclosed in U.S. Published Patent ApplicationNo. 2005/019265A.

The stents described herein can be configured for vascular, e.g.coronary and peripheral vasculature or non-vascular lumens. For example,they can be configured for use in the esophagus or the prostate. Otherlumens include biliary lumens, hepatic lumens, pancreatic lumens,uretheral lumens and ureteral lumens.

Any stent described herein can be dyed or rendered radiopaque byaddition of, e.g., radiopaque materials such as barium sulfate, platinumor gold, or by coating with a radiopaque material. The stent can include(e.g., be manufactured from) metallic materials, such as stainless steel(e.g., 316L, BioDur® 108 (UNS S29108), and 304L stainless steel, and analloy including stainless steel and 5-60% by weight of one or moreradiopaque elements (e.g., Pt, Ir, Au, W) (PERSS®) as described inUS-2003-0018380-A1, US-2002-0144757-A1, and US-2003-0077200-A1), Nitinol(a nickel-titanium alloy), cobalt alloys such as Elgiloy, L605 alloys,MP35N, titanium, titanium alloys (e.g., Ti-6A1-4V, Ti-50Ta, Ti-10Ir),platinum, platinum alloys, niobium, niobium alloys (e.g., Nb-1Zr)Co-28Cr-6Mo, tantalum, and tantalum alloys. Other examples of materialsare described in commonly assigned U.S. application Ser. No. 10/672,891,filed Sep. 26, 2003; and U.S. application Ser. No. 11/035,316, filedJan. 3, 2005. Other materials include elastic biocompatible metal suchas a superelastic or pseudo-elastic metal alloy, as described, forexample, in Schetsky, L. McDonald, “Shape Memory Alloys”, Encyclopediaof Chemical Technology (3rd ed.), John Wiley & Sons, 1982, vol. 20. pp.726-736; and commonly assigned U.S. application Ser. No. 10/346,487,filed Jan. 17, 2003.

The stent can be of a desired shape and size (e.g., coronary stents,aortic stents, peripheral vascular stents, gastrointestinal stents,urology stents, tracheal/bronchial stents, and neurology stents).Depending on the application, the stent can have a diameter of between,e.g., about 1 mm to about 46 mm. In certain embodiments, a coronarystent can have an expanded diameter of from about 2 mm to about 6 mm. Insome embodiments, a peripheral stent can have an expanded diameter offrom about 4 mm to about 24 mm. In certain embodiments, agastrointestinal and/or urology stent can have an expanded diameter offrom about 6 mm to about 30 mm. In some embodiments, a neurology stentcan have an expanded diameter of from about 1 mm to about 12 mm. Anabdominal aortic aneurysm (AAA) stent and a thoracic aortic aneurysm(TAA) stent can have a diameter from about 20 mm to about 46 mm. Thestent can be balloon-expandable, self-expandable, or a combination ofboth (e.g., U.S. Pat. No. 6,290,721).

In embodiments, the tie layer and drug-eluting layer are provided onlyon the abluminal surface, as illustrated. In other embodiments, theseelements are provided as well or only on the adluminal surface and/orcut-face surfaces.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference herein in their entirety.

Still further embodiments are in the following claims.

1. An endoprosthesis, comprising: a body including a ceramic coating ona surface thereof, the ceramic coating having an Sdr of about 10 or lessand an Sq of about 10 or less, a tie layer covalently bonded to theceramic coating, and a polymeric coating adhered to the tie layer. 2.The endoprosthesis of claim 1, wherein the polymeric coating includes adrug.
 3. The endoprosthesis of claim 1, wherein the ceramic coating hasa globular morphology.
 4. The endoprosthesis of claim 1, wherein theceramic coating has surface oxygen content of about 80% or more.
 5. Anendoprosthesis, comprising: a body including a ceramic coating on asurface thereof, the ceramic coating having an Sdr of about 120 to 200and an Sq of about 20 or more, a tie layer non-covalently adhered to theceramic coating, and a polymeric coating adhered to the tie layer. 6.The endoprosthesis of claim 5, wherein the ceramic coating has a definedgrain morphology.
 7. The endoprosthesis of claim 5, wherein the ceramiccoating has a surface oxygen content of about 80% or less.
 8. Theendoprosthesis of claim 1, wherein the ceramic coating comprises amaterial selected from among an oxide and IROX.
 9. The endoprosthesis ofclaim 1, wherein the tie layer is selected from silanes, phosphonates,and titanates.
 10. The endoprosthesis of claim 1, wherein the polymericcoating is adhered to the tie layer by covalent bonding or bynon-covalent adherence.
 11. An endoprosthesis, comprising: a bodyincluding a ceramic coating on a surface thereof, a tie layer covalentlybonded to the ceramic coating, and a polymeric coating adhered to thetie layer, wherein the polymeric coating and the ceramic coating have anadhesion increased about 50% or greater by the tie layer.
 12. A methodof forming an endoprosthesis, comprising: forming a ceramic and anon-ceramic, non-metal overlayer on the ceramic such that, the ceramichas an Sdr of about 10 or less, and the overlayer is covalently bondedto the ceramic, or the ceramic has an Sdr of about 100 or greater, andthe overlayer is non-covalently adhered to the ceramic, or the ceramichas an Sdr between about 10 and 100 and the overlayer is non-covalentlyadhered or covalently bonded to the ceramic.
 13. The method of claim 12,wherein the ceramic having the Sdr of about 10 or less has a globularmorphology.
 14. The method of claim 12, wherein the ceramic having theSdr of about 100 or greater has a defined grain morphology.
 15. Themethod of claim 12, wherein the ceramic is an oxide or IROX.
 16. Themethod of claim 12, wherein the covalent bond is through oxygen moietiesof the ceramic.
 17. The method of claim 12, wherein the overlayer is asilane, phosphate or titanate.
 18. The method of claim 12, furthercomprising forming a polymer layer on the overlayer.
 19. The method ofclaim 18, wherein the polymer layer includes a drug.
 20. The method ofclaim 18, wherein the polymer layer and the ceramic has an adhesionincreased about 10% or greater by the overlayer.
 21. The endoprosthesisof claim 5, wherein the polymeric coating includes a drug.
 22. Theendoprosthesis of claim 5, wherein the ceramic coating comprises amaterial selected from among a oxide and IROX.
 23. The endoprosthesis ofclaim 5, wherein the tie layer is selected from silanes, phosphonates,and titanates.
 24. The endoprosthesis of claim 5, wherein the polymericcoating is adhered to the tie layer by covalent bonding or bynon-covalent adherence.
 25. The endoprosthesis of claim 11, wherein thepolymeric coating includes a drug.
 26. The endoprosthesis of claim 11,wherein the ceramic coating comprises a material selected from among aoxide and IROX.
 27. The endoprosthesis of claim 11, wherein the tielayer is selected from silanes, phosphonates, and titanates.
 28. Theendoprosthesis of claim 11, wherein the polymeric coating is adhered tothe tie layer by covalent bonding or by non-covalent adherence.